Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to powdered preparations containing tiotropium for inhalation, processes for preparing them as well as their use for preparing a pharmaceutical composition for treating respiratory complaints, particularly for treating COPD (chronic obstructive pulmonary disease) and asthma.
• COPD chronic obstructive pulmonary disease
• Tiotropium bromide is known from European Patent Application EP 418 716 A1 and has the following chemical structure:
• Tiotropium bromide is a highly effective anticholinergic with a long-lasting activity which can be used to treat respiratory complaints, particularly COPD (chronic obstructive pulmonary disease) and asthma.
• COPD chronic obstructive pulmonary disease
• tiotropium refers to the free ammonium cation.
• the active substance With active substances which have a particularly high efficacy, only small amounts of the active substance are needed per single dose to achieve the desired therapeutic effect. In such cases, the active substance has to be diluted with suitable excipients in order to prepare the inhalable powder. Because of the large amount of excipient, the properties of the inhalable powder are critically influenced by the choice of excipient. When choosing the excipient its particle size is particularly important. As a rule, the finer the excipient, the poorer its flow properties. However, good flow properties are a prerequisite for highly accurate metering when packing and dividing up the individual doses of preparation, e.g. when producing capsules (inhalettes) for powder inhalation or when the patient is metering the individual dose before using a multi-dose inhaler.
• the particle size of the excipient is very important for the emptying characteristics of capsules when used in an inhaler. It has also been found that the particle size of the excipient has a considerable influence on the proportion of active substance in the inhalable powder which is delivered for inhalation.
• the term inhalable proportion of active substance refers to the particles of the inhalable powder which are conveyed deep into the branches of the lungs when inhaled with a breath. The particle size required for this is between 1 and 10 ⁇ m, preferably less than 6 ⁇ m.
• the aim of the invention is to prepare an inhalable powder containing tiotropium which, while being accurately metered (in terms of the amount of active substance and powder mixture packed into each capsule by the manufacturer as well as the quantity of active substance released and delivered to the lungs from each capsule by the inhalation process) with only slight variations between batches, enables the active substance to be administered in a large inhalable proportion.
• a further aim of the present invention is to prepare an inhalable powder containing tiotropium which ensures good emptying characteristics of the capsules, whether it is administered to the patient using an inhaler, for example, as described in WO 94/28958, or in vitro using an impactor or impinger.
• tiotropium particularly tiotropium bromide
• tiotropium bromide has a therapeutic efficacy even at very low doses imposes further conditions on an inhalable powder which is to be used with highly accurate metering. Because only a low concentration of the active substance is needed in the inhalable powder to achieve the therapeutic effect, a high degree of homogeneity of the powder mixture and only slight fluctuations in the dispersion characteristics from one batch of capsules to the next are essential. The homogeneity of the powder mixture and minor fluctuations in the dispersion properties are crucial in ensuring that the inhalable proportion of active substance is released reproducibly in constant amounts and with the lowest possible variability.
• a further aim of the present invention is to prepare an inhalable powder containing tiotropium which is characterised by a high degree of homogeneity and uniformity of dispersion.
• the present invention also sets out to provide an inhalable powder which allows the inhalable proportion of active substance to be administered with the lowest possible variability.
• the present invention relates to inhalable powders containing 0.04 to 0.8% of tiotropium mixed with a physiologically acceptable excipient, characterised in that the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 ⁇ m and finer excipient with an average particle size of 1 to 9 ⁇ m, the proportion of finer excipient representing 1 to 20% of the total amount of excipient.
• Inhalable powders which contain 0.08 to 0.64%, most preferably 0.16 to 0.4% of tiotropium, are preferred according to the invention.
• tiotropium is meant the free ammonium cation.
• the counter-ion (anion) may be chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate. Of these anions, the bromide is preferred.
• the present invention preferably relates to inhalable powders which contain between 0.048 and 0.96% of tiotropium bromide.
• inhalable powders which contain 0.096 to 0.77%, most preferably 0.19 to 0.48% of tiotropium bromide.
• the tiotropium bromide which is preferably contained in the inhalable powders according to the invention may include solvent molecules during crystallisation.
• the hydrates of tiotropium bromide are used to prepare the tiotropium-containing inhalable powder according to the invention.
• the present invention relates to powders for inhalation which contain between 0.05 and 1% of tiotropium bromide monohydrate.
• inhalable powders which contain 0.1 to 0.8%, most preferably 0.2 to 0.5% of tiotropium bromide monohydrate.
• the inhalable powders according to the invention are preferably characterised in that the excipient consists of a mixture of coarser excipient with an average particle size of 17 to 50 ⁇ m, most preferably 20 to 30 ⁇ m, and finer excipient with an average particle size of 2 to 8 ⁇ m, most preferably 3 to 7 ⁇ m.
• the phrase average particle size used here denotes the 50% value from the volume distribution measured with a laser diffractometer using the dry dispersion method.
• Inhalable powders in which the proportion of finer excipient in the total amount of excipient is from 3 to 15%, most preferably 5 to 10%, are preferred.
• the coarser and finer excipient fractions may consist of chemically identical or chemically different substances, while inhalable powders in which the coarser excipient fraction and the finer excipient fraction consist of the same chemical compound are preferred.
• physiologically acceptable excipients which may be used to prepare the inhalable powders according to the invention include, for example, monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another.
• mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates.
• lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
• the inhalable powders according to the invention may for example be administered using inhalers which meter a single dose from a reservoir by means of a measuring chamber (e.g. according to U.S. Pat. No. 4,570,630A) or by other means (e.g. according to DE 36 25 685 A).
• a measuring chamber e.g. according to U.S. Pat. No. 4,570,630A
• DE 36 25 685 A e.g. according to DE 36 25 685 A
• the inhalable powders according to the invention are packed into capsules (to make so-called inhalettes), which are used in inhalers such as those described in WO 94/28958, for example.
• the inhalable powder according to the invention is to be packed into capsules (inhalettes) in accordance with the preferred application mentioned above, it is advisable to fill the capsules with amounts of from 3 to 10 mg, preferably from 4 to 6 mg of inhalable powder per capsule. These will then contain between 1.2 and 80 ⁇ g of tiotropium. With a preferred filling of 4 to 6 mg of inhalable powder per capsule, the content of tiotropium per capsule is between 1.6 and 48 ⁇ g, preferably between 3.2 and 38.4 ⁇ g, most preferably between 6.4 and 24 ⁇ g. A content of 18 ⁇ g of tiotropium, for example, corresponds to a content of about 21.7 ⁇ g of tiotropium bromide.
• capsules containing 3 to 10 mg of powder for inhalation preferably hold between 1.4 and 96.3 ⁇ g of tiotropium bromide, according to the invention.
• each capsule contains between 1.9 and 57.8 ⁇ g, preferably between 3.9 and 46.2 ⁇ g, most preferably between 7.7 and 28.9 ⁇ g of tiotropium bromide.
• a content of 21.7 ⁇ g of tiotropium bromide for example, corresponds to a content of about 22.5 ⁇ g of tiotropium bromide monohydrate.
• capsules containing 3 to 10 mg of powder for inhalation preferably hold between 1.5 and 100 ⁇ g of tiotropium bromide monohydrate.
• each capsule contains between 2 and 60 ⁇ g, preferably between 4 and 48 ⁇ g, most preferably between 8 and 30 ⁇ g of tiotropium bromide monohydrate.
• the inhalable powders according to the invention are characterised, in accordance with the objective on which the present invention is based, by a high degree of homogeneity in terms of the accuracy of metering of single doses. This is in the range of ⁇ 8%, preferably ⁇ 6%, most preferably ⁇ 4%.
• the inhalable powders according to the invention may be obtained by the method described hereinafter.
• the excipient mixture is prepared from the defined fractions of the coarser excipient and finer excipient. Then the inhalable powder according to the invention is prepared from the excipient mixture and the active substance. If the inhalable powder is to be administered using inhalettes in suitable inhalers, the preparation of the inhalable powders is followed by the manufacture of the powder-filled capsules.
• the powders for inhalation according to the invention are prepared by mixing the coarser excipient fractions with the finer excipient fractions and subsequently mixing the resulting excipient mixtures with the active substance.
• the coarser and finer excipient fractions are placed in a suitable mixing container.
• the two components are preferably added using a granulating sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
• the coarser excipient is put in first and then the finer excipient fraction is added to the mixing container.
• the two components are preferably added in batches, with some of the coarser excipient being put in first and then finer and coarser excipient being added alternately. It is particularly preferred when producing the excipient mixture to sieve in the two components in alternate layers.
• the two components are preferably sieved in alternately in 15 to 45, most preferably 20 to 40 layers each.
• the mixing of the two excipients may take place while the two components are still being added. Preferably, however, mixing is only done once the two components have been sieved in layer by layer.
• the active substance used has an average particle size of 0.5 to 10 ⁇ m, preferably 1 to 6 ⁇ m, most preferably 2 to 5 ⁇ m.
• the two components are preferably added using a granulating sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
• the excipient mixture is put in first and then the active substance is added to the mixing container. During this mixing process the two components are preferably added in batches. It is particularly preferred when producing the excipient mixture to sieve in the two components in alternate layers.
• the two components are preferably sieved in alternately in 25 to 65, most preferably 30 to 60 layers.
• the mixing of the excipient mixture with the active substance may take place while the two components are still being added. Preferably, however, mixing is only done once the two components have been sieved in layer by layer.
• the powder mixture thus obtained may optionally be added once or repeatedly using a granulating sieve and then subjected to another mixing process.
• One aspect of the present invention relates to an inhalable powder containing tiotropium, which may be obtained by the methods described hereinbefore.
• any reference to tiotropium which is the free ammonium cation, corresponds to a reference to tiotropium in the form of a salt (tiotropium salt) which contains an anion as the counter-ion.
• Tiotropium salts which may be used within the scope of the present invention are those compounds which contain chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate, in addition to tiotropium as counter-ion (anion).
• tiotropium bromide is preferred of all the tiotropium salts.
• References to tiotropium bromide within the scope of the present invention should always be taken as references to all possible amorphous and crystalline modifications of tiotropium bromide. These may, for example, include molecules of solvent in their crystalline structure. Of all the crystalline modifications of tiotropium bromide, those which also include water (hydrates) are preferred according to the invention. It is particularly preferable to use tiotropium bromide monohydrate within the scope of the present invention.
• tiotropium bromide which may be prepared as disclosed in EP 418 716 A1
• tiotropium bromide is preferably subjected to another crystallisation step.
• different crystal modifications are obtained. These modifications may be told apart, for example, by DSC (Differential Scanning Calorimetry).
• solvent DSC methanol 228° C. ethanol 227° C. ethanol/water 229° C. water 230° C. isopropanol 229° C. acetone 225° C. ethyl acetate 228° C. tetrahydrofuran 228° C.
• Tiotropium bromide monohydrate has proved particularly suitable for preparing the formulation according to the invention.
• the DSC diagram of tiotropium bromide monohydrate shows two characteristic signals. The first, relatively broad, endothermic signal between 50-120° C. can be attributed to the dehydration of the tiotropium bromide monohydrate to produce the anhydrous form. The second, relatively sharp endothermic peak at 230 ⁇ 5° C. can be put down to the melting of the substance. These data were obtained using a Mettler DSC 821 and evaluated with the Mettler STAR software package. These data, like the other values given in the above Table, were obtained at a heating rate of 10 K/min.
• lactose-monohydrate (200M) is used as the coarser excipient. It may be obtained, for example, from Messrs DMV International, 5460 Veghel/NL under the product name Pharmatose 200M.
• lactose-monohydrate is used as the finer excipient. It may be obtained from lactose-monohydrate 200M by conventional methods (micronising). Lactose-monohydrate 200M may be obtained, for example, from Messrs DMV International, 5460 Veghel/NL under the product name Pharmatose 200M.
• the apparatus is further cooled to 10-15° C. using cold water and crystallisation is completed by stirring for at least one hour.
• the crystals are isolated using a suction drier, the crystal slurry isolated is washed with 9 liters of cold water (10-15° C.) and cold acetone (10-15° C.).
• the crystals obtained are dried in a nitrogen current at 25° C. over 2 hours. Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory)
• the crystalline tiotropium bromide monohydrate thus obtained is micronised by known methods, to bring the active substance into the average particle size which meets the specifications according to the invention.
• the equipment is operated according to the manufacturer's instructions.
• Measuring equipment HELOS Laser-diffraction spectrometer, (SympaTec) Dispersing unit: RODOS dry disperser with suction funnel, (SympaTec) Sample quantity: from 100 mg Product feed: Vibri Vibrating channel, Messrs. Sympatec Frequency of vibrating 40 rising to 100% channel: Duration of sample feed: 1 to 15 sec. (in the case of 100 mg) Focal length: 100 mm (measuring range: 0.9-175 ⁇ m) Measuring time: about 15 s (in the case of 100 mg) Cycle time: 20 ms Start/stop at: 1% on channel 28 Dispersing gas: compressed air Pressure: 3 bar Vacuum: maximum Evaluation method: HRLD
• At least 100 mg of the test substance are weighed onto a piece of card. Using another piece of card all the larger lumps are broken up. The powder is then sprinkled finely over the front half of the vibrating channel (starting about 1 cm from the front edge). After the start of the measurement the frequency of the vibrating channel is varied from about 40% up to 100% (towards the end of the measurement). The time taken to feed in the entire sample is 10 to 15 sec.
• the equipment is operated according to the manufacturer's instructions.
• Measuring equipment Laser diffraction spectrometer (HELOS), Sympatec Dispersing unit: RODOS dry disperser with suction funnel, Sympatec Sample quantity: 50 mg-400 mg Product feed: Vibri Vibrating channel, Messrs. Sympatec Frequency of vibrating channel: 40 rising to 100% Duration of sample feed: 15 to 25 sec. (in the case of 200 mg) Focal length: 100 mm (measuring range: 0.9-175 ⁇ m) Measuring time: about 15 s (in the case of 200 mg) Cycle time: 20 ms Start/stop at: 1% on channel 28 Dispersing gas: compressed air Pressure: 3 bar Vacuum: maximum Evaluation method: HRLD
• the test substance is weighed onto a piece of card. Using another piece of card all the larger lumps are broken up. The powder is then sprinkled finely over the front half of the vibrating channel (starting about 1 cm from the front edge). After the start of the measurement the frequency of the vibrating channel is varied from about 40% up to 100% (towards the end of the measurement). The sample should be fed in as continuously as possible. However, the amount of product should not be so great that adequate dispersion cannot be achieved. The time over which the entire sample is fed in is about 15 to 25 seconds for 200 mg, for example.
• the equipment is operated according to the manufacturer's instructions.
• Measuring equipment Laser diffraction spectrometer (HELOS), Sympatec Dispersing unit: RODOS dry disperser with suction funnel, Sympatec Sample quantity: 500 mg Product feed: VIBRI Vibrating channel, Messrs. Sympatec Frequency of vibrating channel: 18 rising to 100% Focal length (1): 200 mm (measuring range: 1.8-350 ⁇ m) Focal length (2): 500 mm (measuring range: 4.5-875 ⁇ m) Measuring time: 10 s Cycle time: 10 ms Start/stop at: 1% on channel 19 Pressure: 3 bar Vacuum: maximum Evaluation method: HRLD
• test substance About 500 mg of the test substance are weighed onto a piece of card. Using another piece of card all the larger lumps are broken up. The powder is then transferred into the funnel of the vibrating channel. A gap of 1.2 to 1.4 mm is set between the vibrating channel and funnel. After the start of the measurement the amplitude setting of the vibrating channel is increased from 0 to 40% until a continuous flow of product is obtained. Then it is reduced to an amplitude of about 18%. Towards the end of the measurement the amplitude is increased to 100%.
• Gyrowheel mixer 200 L type: DFW80N-4; made by:
• Granulating sieve Quadro Comil; type: 197-S; made by: Messrs Joisten & Kettenbaum, D-51429 Bergisch-Gladbach.
• lactose monohydrate for inhalation 200M
• lactose monohydrate for inhalation 200M
• lactose monohydrate for inhalation 200M
• lactose monohydrate for inhalation 200M
• lactose monohydrate 5 ⁇ m
• the ingredients sieved in are then mixed together (mixing at 900 rpm).
• excipient mixture About 1.1 to 1.7 kg of excipient mixture (1.1) are added to a suitable mixing container through a suitable granulating sieve with a mesh size of 0.5 mm. Then alternate layers of tiotropium bromide monohydrate in batches of about 0.003 kg and excipient mixture (1.1) in batches of 0.6 to 0.8 kg are sieved in. The excipient mixture and the active substance are added in 46 or 45 layers, respectively (tolerance: ⁇ 9 layers).
• the ingredients sieved in are then mixed together (mixing at 900 rpm).
• the final mixture is passed through a granulating sieve twice more and then mixed (mixing at 900 rpm).
• Inhalation capsules having the following composition were produced using the mixture obtained according to Example 1: tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200 M): 5.2025 mg lactose monohydrate (5 ⁇ m): 0.2750 mg hard gelatine capsule: 49.0 mg Total: 54.5 mg
• Inhalation capsules having the composition: tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200 M): 4.9275 mg lactose monohydrate (5 ⁇ m): 0.5500 mg hard gelatine capsule: 49.0 mg Total: 54.5 mg
• the inhalable powder needed to prepare the capsules was obtained analogously to Example 1.
• Inhalation capsules having the composition: tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200 M): 5.2025 mg lactose monohydrate (5 ⁇ m): 0.2750 mg polyethylene capsule: 100.0 mg Total: 105.50 mg
• the inhalable powder needed to prepare the capsules was obtained analogously to Example 1.
• the mean particle size denotes the value in ⁇ m at which 50% of the particles from the volume distribution have a particle size which is smaller than or equal to the value specified.
• Laser diffraction/dry dispersion is used as the method of measurement for determining the total distribution of the particle size distribution.

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• 2008
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